Wolfe would become the sixth starter to suffer a season-ending injury for the Ravens (6-3), who lead the AFC North by a half-game.
"I think Derek's going to be out for the rest of the year, in all honesty. It looks that way," Harbaugh said. "I don't really have any details on it. I can't say I understand it completely."
Harbaugh deferred questions about Wolfe's injury to general manager Eric DeCosta and the team's medical staff.
Wolfe, 31, started the season on injured reserve with back and hip injuries but was designated to return on Oct. 26. After practicing once (a day before the team's bye), Wolfe was not seen on the practice field again by reporters.
The 21-day window to make a decision on Wolfe's status -- to activate him to the 53-man roster or keep him on IR -- ends Tuesday.
"He's not in a place where he's going to be able to play," Harbaugh said.
A nine-year starter in the NFL, Wolfe was re-signed by the Ravens this offseason to a three-year, $12 million contract (including $8.5 million guaranteed). With Wolfe out, Justin Madubuike stepped into the starting lineup, making 16 tackles and one sack thus far.